Projekty

Role of T-type Calcium Channels in Synaptic Physiology

It is established that presynaptic increase in T-type Ca2+ channel
activity in primary nociceptive neurons contributes for the development of painful neuropathy including peripheral diabetic pain. However, the implication of
T-type channel in synaptic activity remains unknown. There is increasing evidence that T-type Ca2+ channels, besides contributing to neuronal electrical activity,
may also participate to the vesicular release of neurotransmitters at the presynaptic nerve terminals, and interestingly enough, we have recently shown that T-type
channels form functional signaling complexes with some of the presynaptic proteins of the vesicular release machinery
(SNARE proteins, for instance syntaxin-1A and SNAP-25).
We are characterizing the biochemical coupling of T-type channels with SNARE proteins and investigate the functional importance of T-type channel / SNARE complexes in the
synaptic physiology of nociceptive neurons to elucidate their role in pain transmission.

Role of Glycosylation in T-type Calcium Channel Function

The cellular and physiological functions supported by ion channels are not only determine by the intrinsic functional properties of the channels embedded
in the plasma membrane but also by the number of channels that are expressed at the cell surface, their dynamic (stability) and more importantly by their
specific expression in subcellular loci. Protein glycosylation is rapidely emerging as a fundamental post-translational mechanism controling those apsects,
and defects in ion channel glycosylation give rise to numerous human disorders. Alteration of T-type channel expression during diabetes has been documented at
the synaptic endings of primary nociceptive neurons, and recent work from our lab and others have shown that T-type Ca2+ channel function and expression at the
plasma membrane is potently regulated by N-linked glycosylation, and depends on extracellular glucose concentration (as it is relevant for diabetes). We are exploring
the role of glycosylation in the sorting and trafficking of T-type channels in nociceptive neurons to better understand their contribution in painfull diabetic neuropathy,
and possibly in other diabetes-related neuronal disorders.

Electrophysiological Aspects of Congenital Channelopathies

In collaboration with clinical molecular genetic labs, we are characterizing new mutations of ion channels found in patients with neuronal and heart
disorders to understand the cause, provide tools for genetic diagnosis, and ideally propose new therapeutic strategies. We are currently working on
various mutations of KCNQ1 and HERG channels that are associated with the cardiac arrhythmia long QT syndrome, and may lead to syncope, cardiac arrest, or sudden death.